Cell Biology

Toward the Chaperome

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Science  01 Dec 2006:
Vol. 314, Issue 5804, pp. 1355
DOI: 10.1126/science.314.5804.1355b

The expression of misfolded or aberrant proteins on the cell surface could wreak havoc with the immune system. Cells have therefore developed an efficient quality-control system, which diverts misfolded membrane and secretory proteins from the secretory pathway by retaining and degrading them at the entry portal to the secretory pathway, the endoplasmic reticulum (ER). One well-studied example of quality control involves the cystic fibrosis transmembrane conductance regulator (CFTR), misfolding of which is responsible for disease in a large proportion of sufferers. However, sometimes quality control is too stringent, and functional, though mutant, proteins are retained. Wang et al. used a systematic approach to examine the folding pathway and protein interaction partners of CFTR and the common disease variant CFTR ΔF508, which, even though functional, is retained in the ER. A variety of chaperone proteins, which help to promote protein folding, are present in the ER, and a chaperome of over 30 proteins involved in CFTR folding and transport was identified from among more than 200 interacting proteins. In particular, Aha1, a Hsp90 co-chaperone ATPase regulator, was found to be important in retaining mutant CFTR. When levels of Aha1 were reduced, mutant CFTR managed to escape from the ER and reached the plasma membrane. Interfering with CFTR-specific chaperone mechanisms may thus be a useful strategy to correct disease, and other protein misfolding diseases might be similarly amenable to equivalent interventions. — SMH

Cell 127, 803 (2006).

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